Dialysis is a procedure for removing waste products from the blood of a patient when the kidneys are unable to do so on their own. Hemodialysis is a form of dialysis in which waste products are removed from the blood by passing the blood along one side of a semi-permeable membrane and passing a specially formulated solution (i.e., dialysate) along the other side of the semi-permeable membrane. The waste materials that are to be removed from the blood pass with the help of diffusion from the blood of the patient to the dialysis fluid through the permeable membrane.
Another form of dialysis is peritoneal dialysis, in which a dialysate is injected into the patient's abdominal cavity, and the waste materials that are to be removed pass through the membranes of the patient's body into the dialysate which is subsequently drained from the abdominal cavity.
The dialysate is an aqueous solution containing various electrolytes. The dialysate generally comprises dissolved sodium chloride, potassium chloride, calcium chloride, acetate ions, dextrose and other constituents in about the same concentration as normal plasma. Urea, creatinine, uric acid, phosphate and other metabolites normally eliminated by the kidneys diffuse from the blood of the patient into the dialysate until the concentration of these compounds are the same in the blood and in the dialysate. The volume of dialysate fluid used is much greater than the blood volume. The great disparity in volume and the replenishment of dialysate with fresh dialysate ensure that metabolites and excess electrolytes are removed almost completely from the blood.
The dialysate is generally prepared from a dialysate concentrate which contains the sodium ions, potassium ions, calcium ions, magnesium ions, chloride ions, acetate ions and dextrose; a bicarbonate solution; and water. The dialysate concentrate, bicarbonate solution and water are generally combined at, or in close proximity to, a dialysis machine.
Patients receiving regular dialysis treatments for chronic renal failure very frequently are also afflicted with anemia. It is believed that prior to the availability of recombinant erythropoietin, a recombinant DNA version of the human erythropoietin protein that stimulates the production of red blood cells, as many as about 90 percent of all kidney dialysis patients experienced debilitating anemia. A primary cause of anemia in dialysis patients is the inability of the kidneys to produce sufficient erythropoietin to generate adequate amounts of red blood cells. Although erythropoietin therapy stimulates red blood cell production and is very often effective at reducing or eliminating anemia, iron deficiencies are also common among dialysis patients and can result in erythropoietin impairment or resistance. Accordingly, in addition to erythropoietin therapy, it will often be necessary and desirable to deliver iron in a biologically available form to the blood of anemic dialysis patients in order to effectively treat the anemia. Further, there is evidence that iron supplementation can reduce the dose of erythropoietin needed to effectively treat anemia, even for patients that do not have an iron deficiency. This can be very important because recombinant erythropoietin is an expensive drug and can cause mild hypertension and flu-like symptoms. Therefore, it is generally desirable to augment erythropoietin therapy with effective iron supplementation.
It is well known that it is very difficult to treat an iron deficiency with orally administered iron supplements. In general, relatively large doses are needed to achieve a desired therapeutic effect. Further oral administration of iron supplements is known to be commonly accompanied by undesirable side effects including nausea, vomiting, constipation and gastric irritation. For these and other reasons, patient noncompliance is also a common problem.
To overcome the above-described problems with oral delivery of iron, a great deal of effort has been directed to developing iron-containing formulations that are suitable for parenteral administration. Parenterally administered formulations are, in general, aqueous solutions of specific formulation components, in which the solution pH is in the range from pH 4 to pH 8. Parenteral administration encompasses administration by intravenous injection, intramuscular injection, or dialysis.
The formulation of iron-containing compositions for parenteral administration is particularly difficult. The solubility of iron compounds in water is strongly dependent on the pH of the solution and the presence of other formulation components. In general, iron salts are soluble in acidic solutions. Conversely, in basic solutions, unless a chelating agent, such as EDTA is present, iron ions will form insoluble oxides and precipitate from the formulation.
In addition, formulation of iron compounds presents added degrees of difficulty related to the redox chemistries of iron and its ability to catalyze oxidation reactions. With respect to redox chemistries, iron has two common oxidation states, the ferrous or iron2+ state and the ferric or iron3+ state. In general, iron compounds in which iron is in its ferrous oxidation state are more soluble in water than are iron compounds in which iron is in its ferric oxidation state. In the presence of reducing agents, iron is known to cycle from its ferric to its ferrous oxidation state and vice versa. If the iron composition has lower solubility when iron is in its ferric oxidation state, redox cycling may cause insoluble precipitates to form in the formulation. In addition, iron ions in solution are highly reactive oxidizing agents and catalysts for oxidation of other formulation components. For example, iron ions in solution are known to oxidize other common parenteral formulation components such as dextrose, polysaccharides, amines, and phenols to degradation products having undesirable properties, such as color, biological activities, and toxicities that are different from those of the unoxidized substances.
In U.S. Pat. No. 2,822,317 to Gulesich and Marlino, aqueous iron-ascorbic acid preparations are disclosed, having as essential ingredients a non-toxic ferrous salt, a polyhydric alcohol, l-ascorbic acid, and water. Exemplary of non-toxic ferrous salts are ferrous sulfate, ferrous lactate, ferrous gluconate, ferrous succinate and ferrous complex salts, such as ferrous glutamate and ferrous choline citrates. The polyhydric alcohols are derived from sugars and have from 5 to 6 carbon atoms. Exemplary polyhydric alcohols are mannitol, sorbitol, and arabitol. The l-ascorbic acid may be present in the free acid form or in the form of a derivative. The preparation of this invention containing the essential ingredients with the adjuncts has a pH in the range of from about 2.0 to about 3.5.
With respect to intravenous administration, iron-dextran (INFED®), which may be obtained from Watson Pharmaceuticals, Corona, Calif., is formulated in water containing 0.9% (by weight) sodium chloride for parenteral administration. [Physicians Desk Reference, 59th edition, 2005, pages 3301-3303]. Iron-dextran is a dextran macromolecule having a molecular weight ranging generally between about 100,000 and about 200,000 to which iron is complexed by both ionic and electrostatic interactions. Iron dextran thus formulated occasionally causes severe allergic reactions, fever and rashes during injection. Parenteral administration intramuscularly is painful and often results in an undesirable discoloration at the injection site. Further, only about half of the iron in iron-dextran is bioavailable after intravenous injection. The fate of the rest is unknown.
Intravenous administration of iron complexes requires venous access and the commercially available intravenously administered iron supplements, such as iron-dextran and ferric gluconate, are relatively expensive and require a great deal of time and skill to administer.
Intraperitoneal delivery of iron-dextran has been used to treat anemia. However, there is evidence that iron-dextran when administered intraperitoneally is stored in macrophages near the peritoneum and could create abnormal changes in the peritoneum.
Other iron preparations which may be administered by injection are taught in U.S. Pat. No. 5,177,068 to Callingham et al., U.S. Pat. No. 5,063,205 to Peters and Raja, U.S. Pat. No. 4,834,983 to Hider et al., U.S. Pat. No. 4,167,564 to Jenson, U.S. Pat. No. 4,058,621 to Hill, U.S. Pat. No. 3,886,267 to Dahlberg et al., U.S. Pat. No. 3,686,397 to Muller, U.S. Pat. No. 3,367,834 to Dexter and Rubin, and U.S. Pat. No. 3,275,514 to Saltman et al., for example. In general, these are formulations of iron bound to polymeric substrates, or chelated by various ligands, saccharates, dextrans, hydrolyzed protein, etc. All have been unsuccessful and/or possess such adverse side effect that practical utilization has not occurred.
It is known to deliver iron to an iron-deficient patient via dialysis using a composition comprising an ionic iron complex. An advantage is that the dialysis treatment delivers iron to the blood at a relatively constant rate throughout the dialysis session. This is because there is negligible free iron in plasma since iron rapidly binds with a apotransferrin to maintain a concentration gradient from dialysate to plasma.
It has been disclosed that preferred forms of iron for use in a dialysate to treat iron deficiency and/or anemia in dialysis patients are noncolloidal ferric compounds, especially ferric pyrophosphate. In particular, it has been proposed to add ferric pyrophosphate to a bicarbonate concentrate which is combined with an acid concentrate and water to provide an iron supplemented dialysate for patients undergoing long-term hemodialysis or peritoneal dialysis for renal failure. Although ferric pyrophosphate is known to be practically insoluble in water, it has been disclosed that ferric pyrophosphate is freely soluble in bicarbonate concentrate. For example, it was disclosed that 1040 milligrams of ferric pyrophosphate may be dissolved in 94.6 liters (25 gallons) of a bicarbonate concentrate to provide an iron pyrophosphate concentration of 11 milligrams per liter in the bicarbonate concentrate. The concentrate may then be combined with the acid concentrate and an appropriate amount of water to generate a dialysate with an iron concentration of 4 micrograms per deciliter.
To prevent stability and/or precipitation problems with dialysate formulations containing iron compounds, admixture of an iron-containing composition with the other formulation components (e.g., bicarbonate concentrate) is completed immediately prior to infusion of the formulation. U.S. Pat. Nos. 6,841,172 and 5,906,978, both to Ash, provide dialysate compositions including an iron complex that is non-polymeric, has a molecular weight less than about 50,000, is soluble in an aqueous medium, and is chemically stable, (i.e., it does not dissociate into iron ions and its other component anions under conditions according to the invention). Exemplary iron complexes of Ash are ferrous gluconate, ferrous sulfate, ferrous fumarate, ferrous citrate, and ferrous succinate. Exemplary of a dialysate composition of this invention is an aqueous solution having dissolved therein sodium (from about 130 to about 150 mEq/L), magnesium (from about 0.4 to about 1.5 mEq/L), calcium (from about 2 to about 4 mEq/L), potassium (from about 1 to about 4 mEq/L), chloride (from about 90 to about 120 mEq/L), acetate (from about 3 to about 5 mEq/L), bicarbonate (from about 30 to about 40 mEq/L), and an iron complex (from about 1 to about 250 microgram/100 mL). Also provided is a dialysate concentrate, prepared for subsequent dilution to a suitable concentration for use as a dialysate, preferably having a concentration about 30 to about 40 times greater than the concentration of the desired dialysate to be administered to the patient. Ash does not teach how to formulate his iron-containing dialysate or dialysate concentrate. The disclosure that the iron-containing dialysate composition may be used without the need to sterilize the iron-containing composition prior to administration indicates that the formulation is completed immediately before parenteral administration of the iron-containing dialysate composition to the patient in order to prevent microbial growth.
U.S. Pat. No. 6,689,275 to Gupta discloses a method of replacing iron losses during dialysis of patients by infusion of a noncolloidal ferric compound, soluble in hemodialysis solutions, during dialysis. A pharmaceutical composition is provided consisting essentially of dialysis solution including a soluble noncolloidal ferric compound, preferably ferric pyrophosphate. A hemodialysis solution is prepared immediately prior to its use by adding ferric pyrophosphate powder from a vial to a bicarbonate concentrate, mixing until dissolution in the bicarbonate concentrate is complete, and then admixing the resulting solution with an acidic dialysate concentrate and water. Alternatively, a pharmaceutical composition of is prepared by adding ferric pyrophosphate powder to an acidic dialysate concentrate, mixing until dissolution in the acidic concentrate is complete, and then admixing the resulting solution with a bicarbonate dialysate concentrate and water.